The invention relates to tramadol analogs that are useful for the treatment of CNS-related disorders including pain, anxiety, depression and attention deficit disorder.
Opioids such as morphine are very effective for the treatment of pain, but can result in very serious adverse effects, including respiratory depression, and addiction and dependency. Less serious side effects include gastrointestinal inhibition effects and obstipation. As a result, the use of such drugs is limited by the possibility of adverse effects. There is, therefore, a need for effective analgesics, which are not associated with these adverse effects.
U.S. Pat. No. 3,652,589, to Flick, discloses a genus of phenol ethers, which are described as having analgesic properties. The genus includes 2-((dimethylamino)methyl)-1-(3-methoxyphenyl)-cyclohexanol), which has been given the name tramadol. The patent also discloses 3-benzyloxyphenyl analogues of tramadol. U.S. Pat. No. 5.733,936 discloses tramadol analogs substituted at the 4-position of the cyclohexane ring.
Tramadol is commercially available from Ortho-McNeil Pharmaceuticals as a racemic mixture of the (R,R)- and (S,S)-enantiomers under the trademark ULTRAM(copyright). It is approved by the United States Food and Drug Administration for treatment of pain, and reportedly does not produce the side effects generally associated with opioids. However, because tramadol is less effective in relieving pain than the opioid drugs, there remains a need for alternative analgesic compounds.
In one aspect, the invention relates to compounds of formula I: 
wherein
R1 is selected from alkyl, aryl, alkylaryl, substituted alkyl, substituted aryl, and substituted alkylaryl;
R2 is selected from hydrogen, hydroxy, cyano, haloalkyl, glycosyl, SO2R5, and OR5;
R3 and R4 are independently selected from hydrogen and lower alkyl, or R3 and R4 taken together with nitrogen form a five- or six-membered heterocyclic or substituted heterocyclic ring; and
R5 is selected from alkyl, aryl, alkylaryl, substituted alkyl, substituted aryl, and substituted alkylaryl.
It has been unexpectedly discovered that compounds of formula I possess unique pharmacological characteristics with respect to stimulation of opiate receptors and increasing monoamine levels, particularly by inhibition of norepinephrine transport. Therefore, these compounds are effective in treating disorders, including CNS-related disorders, modulated by opiate receptor activity and/or monoamine activity, with diminished side effects compared to administration of the current standards of treatment. These disorders include, but are not limited to, acute and chronic pain, affective disorders, including anxiety and depression, and attention deficit disorders.
In the context of the present invention, alkyl is intended to include linear, branched, or cyclic hydrocarbon structures and combinations thereof. Lower alkyl refers to alkyl groups of from 1 to 4 carbon atoms. Examples of lower alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, s-and t-butyl. Preferred alkyl groups are those of C20 or below. Cycloalkyl is a subset of alkyl and includes cyclic hydrocarbon groups of from 3 to 8 carbon atoms. Examples of cycloalkyl groups include c-propyl, c-butyl, c-pentyl, and norbornyl
Alkoxy or alkoxyl refers to groups of from 1 to 8 carbon atoms of a straight, branched, cyclic configuration and combinations thereof attached to the parent structure through an oxygen. Examples include methoxy, ethoxy, propoxy, isopropoxy, cyclopropyloxy, and cyclohexyloxy. Lower alkoxy refers to groups containing one to four carbons.
Acyl refers to groups of from 1 to 8 carbon atoms of a straight, branched, cyclic configuration, saturated, unsaturated and aromatic and combinations thereof, attached to the parent structure through a carbonyl functionality. One or more carbons in the acyl residue may be replaced by nitrogen, oxygen or sulfur as long as the point of attachment to the parent remains at the carbonyl. Examples include acetyl, benzoyl, propionyl, isobutyryl, t-butoxy-carbonyl, and benzyloxycarbonyl. Lower-acyl refers to groups containing one to four carbons.
Aryl and heteroaryl mean a 5- or 6-membered aromatic or heteroaromatic ring containing 0-3 heteroatoms selected from O, N, or S; a bicyclic 9- or 10-membered aromatic or heteroaromatic ring system containing 0-3 heteroatoms selected from O, N, or S; or a tricyclic 13- or 14-membered aromatic or heteroaromatic ring system containing 0-3 heteroatoms selected from O, N, or S; each of which rings is optionally substituted with 1-3 lower alkyl, substituted alkyl, substituted alkynyl, xe2x95x90O, xe2x80x94NO2, halogen, hydroxy, alkoxy, OCH(COOH)2, cyano, xe2x80x94NR1R2, acylamino, phenyl, benzyl, phenoxy, benzyloxy, heteroaryl, or heteroaryloxy; each of said phenyl, benzyl, phenoxy, benzyloxy, heteroaryl, and heteroaryloxy is optionally substituted with 1-3 substituents selected from lower alkyl, alkenyl, alkynyl, halogen, hydroxy, alkoxy, cyano, phenyl, benzyl, benzyloxy, carboxamido, heteroaryl, heteroaryloxy, xe2x80x94NO2 or xe2x80x94NRR (wherein R is independently H, lower alkyl or cycloalkyl, and xe2x80x94RR may be fused to form a cyclic ring with nitrogen); The aromatic 6- to 14-membered carbocyclic rings include, for example, benzene, naphthalene, indane, tetralin, and fluorene; and the 5- to 10-membered aromatic heterocyclic rings include, e.g., imidazole, pyridine, indole, thiophene, benzopyranone, thiazole, furan, benzimidazole, quinoline, isoquinoline, quinoxaline, pyrimidine, pyrazine, tetrazole and pyrazole.
Arylalkyl means an alkyl residue attached to an aryl ring. Examples are benzyl and phenethyl.
Heteroarylalkyl means an alkyl residue attached to a heteroaryl ring. Examples include, e.g., pyridinylmethyl, and pyrimidinylethyl.
Heterocycle or heterocyclic means a cycloalkyl or aryl residue in which one to two of the carbons is replaced by a heteroatom such as oxygen, nitrogen or sulfur. Examples of heterocycles that fall within the scope of the invention include pyrrolidine, pyrazole, pyrrole, indole, quinoline, isoquinoline, tetrahydroisoquinoline, benzofuran, benzodioxan, benzodioxole (commonly referred to as methylenedioxyphenyl, when occurring as a substituent), tetrazole, morpholine, thiazole, pyridine, pyridazine, pyrimidine, thiophene, furan, oxazole, oxazoline, isoxazole, dioxane, and tetrahydrofuran.
Substituted alkyl, aryl, cycloalkyl, or heterocyclyl refer to alkyl, aryl, cycloalkyl, or heterocyclyl wherein up to three H atoms in each residue are replaced with alkyl, aryl, haloalkyl, halogen, hydroxy, loweralkoxy, carboxy, carboalkoxy, carboxamido, cyano, carbonyl, nitro, amino (primary, secondary or tertiary), alkylthio, sulfoxide, sulfone, acylamino, amidino, phenyl, benzyl, heteroaryl, phenoxy, benzyloxy, or heteroaryloxy, or substituted aryl, wherein up to three H atoms in each residue are replaced with alkyl, aryl, haloalkyl, halogen, hydroxy, loweralkoxy, carboxy, carboalkoxy, carboxamido, cyano, carbonyl, nitro, amino (primary, secondary or tertiary), alkylthio, sulfoxide, sulfone, acylamino, amidino, phenyl, benzyl, heteroaryl, phenoxy, benzyloxy, or heteroaryloxy.
Haloalkyl refers to an alkyl residue, wherein one or more H atoms are replaced by halogen atoms; the term haloalkyl includes perhaloalkyl. Examples of haloalkyl groups that fall within the scope of the invention include CH2F, CHF2, and CF3 
Glycosyl means a sugar residue, attached through an ether linkage. Examples of glycosyl groups include glycosyl, fructosyl, mannosyl, and lactosyl.
Any numerical values recited herein include all values from the lower value to the upper value in increments of one unit provided that there is a separation of at least 2 units between any lower value and any higher value. As an example, if it is stated that the amount of a component or a value of a process variable such as, for example, temperature, pressure, time and the like is, for example, from 1 to 90, preferably from 20 to 80, more preferably from 30 to 70, it is intended that values such as 15 to 85, 22 to 68, 43 to 51, 30 to 32 etc. are expressly enumerated in this specification. For values which are less than one, one unit is considered to be 0.0001, 0.001, 0.01 or 0.1 as appropriate. These are only examples of what is specifically intended and all possible combinations of numerical values between the lowest value and the highest value enumerated are to be considered to be expressly stated in this application in a similar manner.
The graphic representations of racemic, ambiscalemic and scalemic or enantiomerically pure compounds used herein are taken from Maehr J. Chem. Ed. 62, 114-120 (1985): solid and broken wedges are used to denote the absolute configuration of a chiral element; wavy lines indicate disavowal of any stereochemical implication which the bond it represents could generate; solid and broken bold lines are geometric descriptors indicating the relative configuration shown but denoting racemic character; and wedge outlines and dotted or broken lines denote enantiomerically pure compounds of indeterminate absolute configuration.
The present invention relates to the genus of compounds of formula I: 
wherein R1 is selected from alkyl, aryl, alkylaryl, substituted alkyl, substituted aryl, and substituted alkylaryl;
R2 is selected from hydrogen, hydroxy, cyano, haloalkyl, glycosyl, SO2R5, and OR5;
R3 and R4 are independently selected from hydrogen and lower alkyl, or R3 and R4 taken together with nitrogen form a five- or six-membered heterocyclic or substituted heterocyclic ring; and
R5 is selected from alkyl, aryl, alkylaryl, substituted alkyl, substituted aryl, and substituted alkylaryl.
Compounds of the genus may exist as a cis- or trans-isomer. In addition, each conformational isomer may exist as one of a pair of enantiomers because two chiral centers are present in the cyclohexane ring. Accordingly, each member of the genus includes two diasteromeric pairs or four individual enantiomers, designated (R,R)xe2x80x94, (S,S)xe2x80x94, (R,S)xe2x80x94, (S,R)xe2x80x94.
In one embodiment, the present invention relates to a subgenus of the compounds of formula I; the compounds of the subgenus have the structure of formula II: 
wherein R1 is selected from alkyl, aryl, alkylaryl, substituted alkyl, substituted aryl, and substituted alkylaryl;
R2 is hydrogen or OR1; and
R3 and R4 are independently selected from hydrogen and lower alkyl, or R3 and R4 taken together with the nitrogen atom form a five- or six-membered heterocyclic or substituted heterocyclic ring.
The present invention particularly relates to several individual compounds of formula I/II. In a first, hereinafter termed O-methyl tramadol (OMT), R1, R3, and R4 are each methyl, and R2 is methoxy. In a second, termed O-desmethyl O-methyl tramadol (ODMOMT), R1, R3, and R4 are each methyl, and R2 is hydroxy. The structures of OMT and ODMOMT are shown below, with tramadol and its O-desmethyl metabolite for comparison. The N-desmethyl analogs of these compounds, that is, where R1 is methyl, R2 is methoxy or OH, and either or both of R3 or R4 are hydrogen, are also of interest. OMT, ODMOMT and the N-desmethyl analogs include both cis- and trans-isomers, all four enantiomers ((R,R)xe2x80x94, (S,S)xe2x80x94, (R,S)xe2x80x94, and (S,R)xe2x80x94) racemic mixtures thereof and racemic mixtures enriched to any degree in an enantiomer. 
Other specific compounds of formula I that are of particular interest include the following. 
Compounds of formula I are useful for treating disorders modulated by opiate receptor activity and/or monoamine activity. Accordingly, the present invention relates to a method for such treatment, comprising administering to a mammal in need thereof a therapeutically effective amount of a compound of formula I, or a pharmaceutically acceptable salt thereof. In particular, the compound of formula I may be O-methyl tramadol or O-desmethyl O-methyl tramadol. As used herein, the term disorder modulated by opiate receptor activity and/or monoamine activity refers to a disorder, disease or condition opiate receptor activity and/or monoamine activity is an effective means of alleviating the disorder or one or more of the biological manifestations of the disease or disorder; or interferes with one or more points in the biological cascade leading to the disorder or responsible for the underlying disorder; or alleviates one or more symptoms of the disorder. Thus, disorders subject to modulation include those for which:
the lack of opiate receptor activity and/or monoamine activity is a cause of the disorder or one or more of the biological manifestations, whether the activity was altered genetically, by infection, by irritation, by internal stimulus or by some other cause;
the disease or disorder or the observable manifestation or manifestations of the disease or disorder are alleviated by opiate receptor activity and/or monoamine activity. The lack of opiate receptor activity and/or monoamine activity need not be causally related to the disease or disorder or the observable manifestations thereof; and/or
opiate receptor activity and/or monoamine activity interferes with part of the biochemical or cellular cascade that results in or relates to the disease or disorder. In this respect, the opiate receptor activity and/or monoamine activity alters the cascade, and thus controls the disease, condition or disorder.
Disorders modulated by opiate receptor activity and/or monoamine activity include acute and chronic pain, affective disorders, including depression and anxiety, behavioral disorders, including attention deficit disorders, eating disorders, cerebral function disorders, substance abuse, sexual dysfunction, and urinary incontinence.
As noted above, it has been found that compounds of formula I, particularly OMT, ODMOMT, and their N-desmethyl analogs are effective analgesics. The compounds provide relief of chronic and acute pain while avoiding the side effects associated with opioid drugs, particularly respiratory depression. Accordingly, the present invention also relates to a method for relieving acute and chronic pain. The method comprises administering to a mammal in need thereof a therapeutically effective amount of a compound of formula I or of a pharmaceutically acceptable salt thereof. In particular, OMT and/or ODMOMT may be administered.
It has also been found that compounds of formula I are effective for the treatment of affective disorders. Affective disorders are defined as a group of disorders characterized by a disturbance of mood, accompanied by a full or partial manic or depressive symptom. (Tabor""s Medical Dictionary) The group includes, but is not limited to depression, anxiety disorders, bipolar disorder, chronic fatigue disorder, seasonal affective disorder, premenstrual syndrome, perimenopause, menopause and male menopause. Depression is characterized by changes in mood, and by feelings of intense sadness or pessimistic worry. Symptoms include insomnia, anorexia, mental slowing and loss of drive, enthusiasm, and libido. These disorders are additionally characterized in that increasing monoamine levels, especially norepinephrine, reduces symptoms. Accordingly, the present invention also relates to a method for treating affective disorders, including depression. The method comprises administering to a mammal in need thereof a therapeutically effective amount of a compound of formula I, or a pharmaceutically acceptable salt thereof.
The compounds of formula I are also effective for treating behavioral disorders, which are defined as disorders affecting one""s behavior resulting in inappropriate actions in learning and social situations. Behavioral disorders include attention deficit disorder (ADD). The term ADD, as used herein, includes both attention deficit disorder and attention deficit disorder with hyperactivity (ADHD), and is used in accordance with its accepted meaning in the art. (See, for example, Diagnostic and Statistical Manual of Mental Disorders, Revised, Fourth Ed., (DSM-III-R), American Psychiatric Assocation, 1997.) As used herein, the term attention deficit disorder includes disruptive behavior disorder as characterized in DSM-IV-R as categories 314.xx (including 314.01, 314.00 and 314.9), 312.xx and 313.xx. The skilled artisan will recognize that there are alternate nomenclatures, nosologies, and classification systems for pathological conditions and that these systems evolve with medical scientific progress. Methylphenidate (RITALIN(copyright)) is typically the drug of choice for the treatment and/or prevention of ADD. Dextroamphetamine, tricyclic antidepressants, for example, imipramine, caffeine, and other psychostimulants such as pemoline and deanol, are less preferred alternatives to methylphenidate. Common side effects of methylphenidate include sleep disturbances, including insomnia, depression or sadness, headache, stomachache, suppression of appetite, elevated blood pressure, and, with large continuous doses, a reduction of growth. Accordingly, alternate means of treating or preventing attention deficit disorders would be of great benefit.
The compounds of formula I are also effective for treating eating disorders. Eating disorders are defined as a disorder of one""s appetite or eating habits or of inappropriate somatotype visualization. Eating disorders include bulimia, anorexia, obesity and cachexia.
The compounds of formula I are also effective for treating cerebral function disorders. The term cerebral function disorder, as used herein, includes cerebral function disorders involving intellectual deficits such as senile dementia, Alzheimer""s type dementia, memory loss, amnesia/amnestic syndrome, epilepsy, disturbances of consciousness, coma, lowering of attention, speech disorders, Parkinson""s disease, Lennox syndrome, autism, hyperkinetic syndrome and schizophrenia. Also within the meaning of the term are disorders caused by cerebrovascular diseases including cerebral infarction, cerebral bleeding, cerbral arteriosclerosis, cerebral venous thrombosis, head injuries, and the like, where symptoms include disturbance of consciousness, senile dementia, coma, lowering of attention, and speech disorders.
The compounds of formula I are also effective for treating substance abuse. The term substance abuse includes addiction to cocaine, heroin, nocotine, alcohol, anxiolytic and hypnotic drugs, cannabis (marijuana), amphetamines, hallucinogens, phenylcyclidine, volatile solvents, and volatile nitrites. Nicotine addiction includes nicotine addiction of all known forms, such as smoking cigarettes, cigars and/or pipes, and addiction to chewing tobacco.
The compounds of formula I are also effective for treating sexual dysfunction (e.g., erectile dystunction and female sexual dysfunction). The term sexual dysfuntion, as used herein, encompases male sexual dysfunction, or erectile dysfunction, and female sexual dysfunction, including orgasmic dysfunction related to clitoral disturbances. The term erectile dysfunction as used herein means an inability to achieve penile erection or ejaculation or both, or an inability to obtain or sustain an erection adequate for intercourse. The relative activity, potency and specificity of a compound of formula I in the treatment of sexual dysfunction can be assessed by determination of an IC50 value, as described in U.S. Pat. No. 5,656,629. Briefly, the cGMP-PDE and other PDE isozymes are isolated from cardiovascular tissues (heart and aorta) of various animal species and man by anion-exchange and affinity chromatography as described by Silver et al., Sec. Messeng. Phos., 13: 13-25 (1991) PDE activity, in the presence and absence of test compounds is determined essentially as described by Thompson et al., Adv. Cyclic Nucleotide Res., 10:69-92. To determine the potency and selectivity of compounds as PDE inhibitors, compounds are screened for their effect on cyclic nucleotide hydrolysis at 10 xcexcM. If 50% inhibition of PDE activity is observed, an IC50 value is calculated (concentration-response curves as described by Tallarida and Murray, Manual of Pharmacologic Calculations with Computer Programs, Procedure 8, Graded Dose-response, pp. 14-19, Springer-Verlag, New York, 1981. The test provides an estimate of relative activity, potency and, through a measure of specificity, an estimate of the therapeutic index.
The compounds of formula I are also effective for treating urinary incontinence, including, for example, bladder detrusor muscle instability incontinence, stress incontinence, urge incontinence, overflow incontinence, enuresis, and post-prostectomy incontinence. Urinary incontinence can be caused by uncontrolled or unstable bladder contractions, particularly of the bladder detrusor muscle, which serves to force fluids out of the bladder. Bladder detrusor muscle instability may result in, for example, stress incontinence or urge incontinence, or combinations thereof, and/or enuresis. The major proportion of the neurohumeral stimulus for physiologic bladder contraction is acetylcholine-induced stimulation of postganglionic muscarinic receptor sites on bladder smooth muscle.
The present invention also relates to pharmaceutical compositions containing a therapeutically effective amount of one or more compounds of formula I, or a pharmaceutically acceptable salt thereof. A pharmaceutically acceptable carrier may also be included. Other therapeutic ingredients may also be included.
The term pharmaceutically acceptable salts refer to salts prepared from pharmaceutically acceptable non-toxic acids including inorganic acids and organic acids. Examples of acids that form pharmaceutically acceptable salts with compounds of Formula I include acetic acid, benzenesulfonic (besylate) acid, benzoic acid, camphorsulfonic acid, citric acid, ethenesulfonic acid, fumaric acid, gluconic acid, glutamic acid, hydrobromic acid, hydrochloric acid, isethionic acid, lactic acid, maleic acid, malic acid, mandelic acid, methanesulfonic acid, mucic acid, nitric acid, pamoic acid, pantothenic acid, phosphoric acid, succinic acid, sulfuric acid, tartaric acid and p-toluenesulfonic acid. The hydrochloric acid salt is particularly preferred.
Any suitable route of administration may be employed for providing the patient with an effective dosage of a compound of Formula I. For example, oral, rectal, parenteral (including subcutaneous, intramuscular, and intravenous) routes may be employed. Dosage forms include tablets, troches, dispersions, suspensions, solutions, capsules and patches. In particular, the composition may be formulated for oral administration, and may be in the form of a tablet or capsule.
Pharmaceutically acceptable carriers for use in the compositions of the present invention may take a wide variety of forms, depending on the forms preparation desired for administration, for example, oral or parenteral (including intravenous). In preparing the composition for oral dosage form, any of the usual pharmaceutical media may be employed, such as, water, glycols, oils, alcohols, flavoring agents, preservatives, and coloring agents in the case of oral liquid preparation, including suspension, elixirs and solutions. Carriers such as starches, sugars, microcrystalline cellulose, diluents, granulating agents, lubricants, binders and disintegrating agents may be used in the case of oral solid preparations such as powders, capsules and caplets, with the solid oral preparation being preferred over the liquid preparations. Preferred solid oral preparations are tablets or capsules, because of their ease of administration. If desired, tablets may be coated by standard aqueous or nonaqueous techniques. Oral and parenteral sustained release dosage forms may also be used.
Oral syrups, as well as other oral liquid formulations, are well known to those skilled in the art, and general methods for preparing them are found in any standard pharmacy school textbook, for example Remington: The Science and Practice of Pharmacy. Chapter 86 of the 19 th edition of Remington entitled xe2x80x9cSolutions, Emulsions, Suspensions and Extractsxe2x80x9d describes in complete detail the preparation of syrups (pages 1503-1505) and other oral liquids. Similarly, sustained or controlled release formulation is well known in the art, and Chapter 94 of the same reference, entitled xe2x80x9cSustained-Release Drug Delivery Systems,xe2x80x9d describes the more common types of oral and parenteral sustained-release dosage forms (pages 1660-1675.) The relevant disclosure, Chapters 84 and 96, is incorporated herein by reference. Because they reduce peak plasma concentrations, as compared to conventional oral dosage forms, controlled release dosage forms are particularly useful for providing a therapeutic plasma concentration of a compound of formula I while avoiding the side effects associated with high peak plasma concentrations that occur with conventional dosage forms.
The compositions may be conveniently presented in unit dosage form and prepared by any of the methods well known in the art of pharmacy. Preferred unit dosage formulations are those containing an effective dose, or an appropriate fraction thereof, of the active ingredient, or a pharmaceutically acceptable salt thereof. The magnitude of a prophylactic or therapeutic dose typically varies with the nature and severity of the condition to be treated and the route of administration. The dose, and perhaps the dose frequency, will also vary according to the age, body weight and response of the individual patient. In general, the total daily dose ranges from about 10 mg per day to about 1000 mg per day, preferably about 20 mg per day to about 500 mg per day, and more preferably, about 50 mg per day to about 250 mg per day, in single or divided doses. It is further recommended that children, patients over 65 years old, and those with impaired renal or hepatic function, initially receive low doses and that the dosage be titrated based on individual responses and blood levels. It may be necessary to use dosages outside these ranges in some cases, as will be apparent to those in the art. Further, it is noted that the clinician or treating physician knows how and when to interrupt, adjust or terminate therapy in conjunction with individual patient""s response.
Compounds of formula I having a cis-configuration may be synthesized from tramadol, which is commercially available as a racemic mixture of the (R,R)- and (S,S)-enantiomers. The enantiomers may be resolved using a modification of the procedure described in U.S. Pat. No. 3,652,589, as shown in Scheme 1, using D- or L-dibenzyl tartaric acid (DBTA) as appropriate. 
Other methods that may be used for the resolution of enantiomers include formation of diastereoisomeric salts or complexes or derivatives which may be separated, for example, by crystallization, gas-liquid or liquid chromatography; selective reaction of one enantiomer with an enantiomer-specific reagent, for example, enzymatic oxidation or reduction, followed by separation of the modified and unmodified enantiomers; and gas-liquid or liquid chromatography in a chiral environment, for example, on a chiral support, such as silica with a bound chiral ligand or in the presence of a chiral solvent. It will be appreciated that where the desired enantiomer is converted into another chemical entity by one of the separation procedures described above, a further step is typically required to liberate the desired enantiomeric form. Alternatively, specific enantiomer may be synthesized by asymmetric synthesis using optically active reagents, substrates, catalysts or solvents, or by converting one enantiomer to the other by asymmetric transformation.
Schemes 2 and 3 illustrate preparation of enantiomerically pure OMT and ODMOMT, starting from either enantiomerically pure cis-tramadol or from a racemic mixture of the (R,R)- and (S,S)-enantiomers. In Scheme 2, the hydroxy group at the 2-position of the cyclohexane ring of racemic tramadol, or one of its enantiomers, is methylated to yield a mixture of the cis- and trans-isomers of OMT. The cis-isomer may be isolated by crystallization. Scheme 3 shows procedure for this synthesis of ODMOMT by demethylation of OMT (from Scheme 2) using Ph2PH and an alkyl lithium compound. Other cis-isomers of compounds of formula I may be synthesized from tramadol, using known procedures. 
Procedures for the synthesis of compounds of formula I having a trans-configuration are illustrated in Schemes 4 through 8. An enantiomerically selective preparation of trans-tramadol is shown in Schemes 4-6. Scheme 7 shows demethylation of trans-tramadol using DIBAL. Preparation of racemic trans-OMT is shown in Scheme 8. Other trans-isomers of compounds of formula I may be synthesized from compounds shown in Schemes 4 or 6, for example, trans-N,N-demethyltramadol, or the nitrile analog shown in Scheme 4, using known procedures. 
N-Desmethyl tramadol analogs may be prepared in quantities suitable for continued research and biological testing, starting with racemic tramadol hydrochloride. The synthsis is illustrated schematically below; products are designated: 1) desmethyltramadol (DMT) 2) desmethyl-O-desmethyltramadol (DMODMT) 3) desmethyl-O-methyltramadol (DMOMT) and 4) desmethyl-O-desmethyl-O-methyltramadol (DMODMOMT). 
Tramadol hydrochloride is treated with aqueous potassium carbonate to provide racemic tramadol free-base. Tramadol hydrochloride is resolved with dibenzoyl tartrate to provide quantities of (R,R)- and (S,S)-tramadol.
Preparation of DMODMT is shown in Scheme 9. Tramadol free-base is N-demethylated with DEAD to provide DMT. The phenol functionality is then deprotected with DIBAL to provide DMODMT. 
Preparation of DMODMOMT is shown in Scheme 10. To access the O-methylated compounds, the reactive nitrogen had to be first masked as the benzonium salt. This compound may then be methylated easily to provide the O-methyl framework. Removal of the N-benzyl group is effected with hydrogen gas over palladium to provide O-methyltramadol (OMT). OMT is demethylated with chloroethyl chloroformate to furnish DMOMT. The aryl-methyl ether is cleaved with LiPPh2 and produced DMODMOMT. 
A cyano analog of tramadol may be prepared according to the procedure illustrated in Scheme 11. 